F17464 is a new dopamine receptor antagonist that recently demonstrated antipsychotic activity in a proof of concept study in schizophrenic patients under acute exacerbation. The compound has a unique profile with high affinity for hD3 receptors (Ki = 0.17 nM) and lower affinity for hD2L (Ki = 12.1 nM) and hD2S (Ki = 6.5 nM). F17464 exhibits also high affinity for h5-HT1A receptors (Ki = 0.16 nM). F17464 is a hD3 antagonist (pKB = 9.13), hD2S very week partial agonist (pKB = 7.87, emax 8% of DA stimulated in ERK assay) and a 5-HT1A partial agonist (pEC50 = 7.99). F17464 exhibits consistent affinities for rat striatal D2 (Ki = 4.8 nM) and for rat hippocampal 5-HT1A receptors (Ki = 1.14 nM). Neurochemical studies show that F17464 ip (1 h post-dose) produces a significant dose–dependent increase in the levels of DOPAC and HVA in the frontal cortex, caudate-putamen and limbic forebrain and an increase in 3-MT levels in the latter two regions with no changes in total DA content. The effect is significant at the doses of 0.63–2.5 mg/kg ip (PK/PD data will be provided). This pattern of DA metabolite changes is similar to that described for several antipsychotic drugs in rodents and it is indicative of a cortical effect of F17464. F17464 has a very low cataleptogenic activity in rats and mice and does not induce serotoninergic signs typical of 5-HT1A. F17464 is therefore a novel a D3 preferential antipsychotic with a unique mechanism of action and receptor affinity profile and a consistent effect in neurochemistry studies in rodents.
Disclosure of interest
The authors have not supplied their declaration of competing interest.